The development of fluorine substituted volatile anesthetics has revolutionized surgery. The fluorine substituted volatile anesthetics which are now available have properties which approach ideal drug behavior. In use, the fluorinated volatile anesthetics are inhaled by a patient, dissolve in the patient's blood and rapidly produce unconsciousness. Unconsciousness is maintained while administration is continued, and upon discontinuing administration they are exhaled. As the anesthetics are exhaled, the patient returns to consciousness. An ideal fluorine containing volatile anesthetic produces quality anesthesia, has rapid onset, rapid recovery, muscle relaxation, sedation, and analgesia.
Commercially available volatile fluorinated anesthetics include desflurane (CF3CHFOCHF2), enflurane (CHClFCF2OCHF2), halothane (CF3CHBrCl), isoflurane (CF3CHClOCHF2) and sevoflurane ((CF3)2CHOCH2F). The physical properties of volatile fluorinated anesthetics are important to the anesthesiologist These physical properties include boiling point, specific gravity, vapor density, vapor pressure, oil/gas partition coefficient and blood/gas partition coefficient (percent of the anesthetic found in a known quantity of blood versus the percent found in a known volume of atmosphere above the blood sample). The blood-gas partition coefficient is considered to be particularly important, as it serves as a significant aid in predicting the time a patient needs to awaken from anesthesia.
Although each of the molecules depicted above has its own unique characteristics that provide a set of parameters needed to commercially develop it as an anesthetic, the chemical properties and chemical purity of the fluorinated volatile anesthetic are particularly important. Of particular interest is the general reactivity of the compound, as well as the stability of the anesthetic to light, air, soda-lime, and a variety of metals and nonmetallic materials which may contact the anesthetic during a normal surgical procedure. Additionally, the minimum flammable concentration of the anesthetic in pure oxygen, or 70% nitrous oxide and 30% oxygen, must be determined to ensure that it is well out of the range of the effective concentration of anesthetic used in surgery.
The chemical purity of the fluorine substituted volatile anesthetic is of utmost importance, requiring clean methods of production and extensive manufacturing controls. Additionally, the synthesis of these anesthetics requires consideration of many factors not normally encountered in the medicinal chemistry arena, i.e., the need to produce millions of pounds of pharmaceuticals with the highest standards of purity. In contrast to volatile anesthetics, many drugs are typically administered in milligram quantities. As a result, a fraction of a percent of an impurity in a few milligrams of a drug can be easily eliminated by the patient. However, since 10 to 50 grams of a volatile anesthetic are typically used during the course of a normal surgical procedure, the same concentration of impurity can reach a toxic level. Accordingly, it is highly desirable to find synthetic routes that give high purity fluorine substituted volatile anesthetics.
The compound 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether (also known as sevoflurane) is an important volatile anesthetic agent particularly suited for administration to patients during outpatient surgery. Sevoflurane is known to provide patients with a rapid rate of recovery from the anesthesia. An additional advantage of this anesthetic agent is that it can be used as an induction agent since it is not pungent and allows a rapid and smooth induction without breath holding or laryngospasm as may occur with other inhalation agents. A smooth uneventful induction is especially valuable for pediatric anesthesia where the use of intravenous induction agents can result in numerous problems and is often contraindicated.
A number of methods of preparing 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether have been described. U.S. Pat. No. 3,683,092 describes four methods of preparation, three of which start with 1,1,1,3,3,3-hexafluoroisopropyl methyl ether. This ether is a well known compound, the preparation of which is described in U.S. Pat. No. 3,911,024. The specific reaction chemistries disclosed in the '092 patent are summarized below:(CF3)2CHOCH3+Cl2→(CF3)2CHOCH2Cl→(CF3)2CHOCH2F  (1)In equation (1), the chlorinated either is converted to the fluorinated form by reacting it in the presence of potassium fluoride (KF) in sulfolane.6(CF3)2CHOCH2Cl+2BrF3→6(CF3)2CHOCH2F+3Cl2+Br2  (2)3(CF3)2CHOCH3+2BrF3→3(CF3)CHOCH2F+3HF+Br2  (3)None of the three routes above are suitable for economical large scale manufacture. The method employing potassium fluoride requires high temperatures and long reaction times. The other two methods require the use of expensive and dangerous bromine trifluoride.
The fourth method described in the '092 patent starts with 1,1,1,3,3,3-hexafluoroisopropanol which is reacted with hydrogen fluoride and formaldehyde in a fluoromethylation reaction as shown in reaction (4):(CF3)2CHOH+CH2O+HF→(CF3)2CHOCH2F+H2O  (4)Although reaction (4) uses economical reagents and is potentially attractive in a commercial synthesis, yields are poor due to the formation of polyether byproducts.
Several other methods for preparation of 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether have also been reported. For example, a direct fluorination reaction using elemental fluorine in argon was reported in U.S. Pat. No. 3,897,502. The reaction is shown in equation (5) below:(CF3)2CHOCH3→(CF3)2CHOCH2F  (5)The reaction of equation (5) is carried out in the presence of fluorine (F2) and argon. The method of the '502 patent is not suitable for large scale commercial synthesis since yields are not good and the method uses elemental fluorine, an expensive and difficult to handle reagent.
U.S. Pat. No. 4,874,901 discloses a halogen exchange reaction using NaF under supercritical conditions (temperature: 250–325° C., pressure: 60 to 80 atmospheres) as described in reaction (6) below:(CF3)2CHOCH2Cl+NaF→(CF3)2CHOCH2F  (6)The utility of the method of the '901 patent is limited because of the extremely high temperatures and pressures required.
A fluorodecarboxylation synthesis was reported in U.S. Pat. No. 4,996,371 as shown in equation (7):(CF3)2CHOH+ClCH2COOH→(CF3)2CHOCH2COOH+BrF3→(CF3)2CHOCH2F  (7)Again, the method of the '371 patent uses the expensive and dangerous bromine trifluoride reactant and is not suitable for commercial manufacture.
Another even more expensive synthesis using large quantities of bromine trifluoride is described in U.S. Pat. No. 4,874,902. The reaction chemistry of the '902 patent is exemplified below:(CCl3)2CHOH→(CCl3)2CHOCH3→(CCl3)2CHOCH2Cl+BrF3→(CF3)2CHOCH2F  (8)
A further method of synthesis claimed to be suitable for manufacture of 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether on a large scale is described in U.S. Pat. No. 4,250,334; this method starts with hexafluoroisopropanol and uses hydrogen fluoride and sulfuric acid as reactants as shown in equation (9):(CF3)2CHOH+CH2O+HF+H2SO4→(CF3)2CHOCH2F  (9)Although yields of 90% are claimed, conversions are only 33 to 38%. The method of the '334 patent suffers the further disadvantage that a large stoichiometric excesses of formaldehyde, hydrogen fluoride, and sulfuric acid are required. The use of such excesses could result in large amounts of hazardous waste byproducts containing formaldehyde, a known carcinogen. It is also possible that this waste product would contain bis-fluoromethyl ether, structurally related to the carcinogenic bis-chloromethyl ether.
Synthesis of fluoroethers has been reported in DE 2823969 A1. As taught in that publication, a number of chloromethyl ethyl and chloromethyl n-propyl ethers were reacted with amines and anhydrous hydrogen fluoride to give the corresponding fluoromethyl ethers. Example 1 of the '969 publication is given in equation (10):CF3CHFCF2OCH2Cl+(Et)3N+HF→CF3CHFCF2OCH2F  (10)However, the reaction of the more sterically hindered and predictably less reactive isopropyl chloromethylethers was not reported.
It would therefore be desirable to have a synthesis of 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether which does not use expensive reagents, such as elemental fluorine or bromine trifluoride, does not involve the use of high temperatures and pressures, and does not create large amounts of hazardous waste as a byproduct.